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Published online
doi:10.1083/jcb.200901104
The Journal of Cell Biology, Vol. 185, No. 3, 439-457
The Rockefeller University Press, 0021-9525 $30.00
© Norrmén et al.
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Article

FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1



Camilla Norrmén1, Konstantin I. Ivanov1, Jianpin Cheng1, Nadine Zangger4, Mauro Delorenzi4, Muriel Jaquet5, Naoyuki Miura6, Pauli Puolakkainen2, Valerie Horsley7, Junhao Hu8, Hellmut G. Augustin8, Seppo Ylä-Herttuala9, Kari Alitalo1,3, and Tatiana V. Petrova1,5

1 Molecular Cancer Biology Program, Biomedicum Helsinki, 2 Department of Surgery, Helsinki University Central Hospital, and 3 Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, 00014 Helsinki, Finland
4 Swiss Institute of Bioinformatics, Génopode, 1015 Lausanne, Switzerland
5 Division of Experimental Oncology, Multidisciplinary Oncology Center, University of Lausanne, 1066 Epalinges, Switzerland
6 Department of Biochemistry, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Japan
7 Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065
8 Joint Research Division of Vascular Biology, Centre for Biomedicine and Medical Technology Mannheim, Heidelberg University and German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
9 A.I. Virtanen Institute, University of Kuopio, 70211 Kuopio, Finland

Correspondence to Tatiana V. Petrova: tatiana.petrova{at}unil.ch

The mechanisms of blood vessel maturation into distinct parts of the blood vasculature such as arteries, veins, and capillaries have been the subject of intense investigation over recent years. In contrast, our knowledge of lymphatic vessel maturation is still fragmentary. In this study, we provide a molecular and morphological characterization of the major steps in the maturation of the primary lymphatic capillary plexus into collecting lymphatic vessels during development and show that forkhead transcription factor Foxc2 controls this process. We further identify transcription factor NFATc1 as a novel regulator of lymphatic development and describe a previously unsuspected link between NFATc1 and Foxc2 in the regulation of lymphatic maturation. We also provide a genome-wide map of FOXC2-binding sites in lymphatic endothelial cells, identify a novel consensus FOXC2 sequence, and show that NFATc1 physically interacts with FOXC2-binding enhancers. As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention.

K.I. Ivanov and J. Cheng's present address is Division of Experimental Oncology, Multidisciplinary Oncology Center, University of Lausanne, 1066 Epalinges, Switzerland.

V. Horsley's present address is Dept. of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520.

Abbreviations used in this paper: CEAS, cis-regulatory element annotation system; ChIP, chromatin immunoprecipitation; CsA, cyclosporine A; EMSA, electrophoretic mobility shift assay; FDR, false discovery rate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; iLEC, intestinal LEC; LEC, lymphatic endothelial cell; MAT, model-based analysis of tiling array; NFAT, nuclear factor of activated T cells; SLC, secondary lymphoid chemokine; SMA, smooth muscle actin; SMC, smooth muscle cell.

© 2009 Norrmén et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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